Manipulation of a genetically and spatially defined sub-population of BDNF-expressing neurons potentiates learned fear and decreases hippocampal-prefrontal synchrony in mice
Manipulation of a genetically and spatially defined sub-population of BDNF-expressing neurons potentiates learned fear and decreases hippocampal-prefrontal synchrony in mice
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DOI：
10.1038/s41386-019-0429-1
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发表时间：
2019-12-01
影响因子：
7.6
通讯作者：
Martinowich, Keri
中科院分区：
文献类型：
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作者：
Hallock, Henry L.;Quillian, Henry M.;Martinowich, Keri
脑源性神经营养因子（BDNF）信号调节海马（HC）和前额叶皮质（PFC）的突触可塑性，并与啮齿动物的恐惧记忆表达有广泛的联系。值得注意的是，破坏启动子IV衍生转录本的BDNF产生增强了小鼠的恐惧表达，并降低了恐惧相关的HC-PFC同步，这表明启动子IV的BDNF转录在恐惧记忆检索过程中HC-PFC功能中起关键作用。为了更好地理解启动子iv衍生的BDNF如何控制HC-PFC连接和恐惧表达，我们创建了一个病毒构建体，选择性地靶向表达启动子iv衍生的BDNF转录本的细胞（“p4细胞”），用于他莫昔芬诱导的cre介导重组(AAV8-p4Bdnf-ER（T2)CreER(T2)-PEST）。利用这种结构，我们发现在恐惧表达过程中，腹侧海马（vHC） p4细胞被募集，这些细胞的激活导致小鼠的恐惧表达过度，同时vHC- pfc同步被破坏。我们的数据强调了这种新结构如何用于询问基因定义的细胞类型，这些细胞类型选择性地促进bdnf依赖行为。
Brain-derived neurotrophic factor (BDNF) signaling regulates synaptic plasticity in the hippocampus (HC) and prefrontal cortex (PFC), and has been extensively linked with fear memory expression in rodents. Notably, disrupting BDNF production from promoter IV-derived transcripts enhances fear expression in mice, and decreases fear-associated HC-PFC synchrony, suggesting that Bdnf transcription from promoter IV plays a key role in HC-PFC function during fear memory retrieval. To better understand how promoter IV-derived BDNF controls HC-PFC connectivity and fear expression, we generated a viral construct that selectively targets cells expressing promoter IV-derived Bdnf transcripts ("p4-cells") for tamoxifen-inducible Cre-mediated recombination (AAV8-p4Bdnf-ER(T2)CreER(T2)-PEST). Using this construct, we found that ventral hippocampal (vHC) p4-cells are recruited during fear expression, and that activation of these cells causes exaggerated fear expression that co-occurs with disrupted vHC-PFC synchrony in mice. Our data highlight how this novel construct can be used to interrogate genetically defined cell types that selectively contribute to BDNF-dependent behaviors.